Lipoprotein Lipase S447V polymorphism associates with VLDL, LDL and HDL diameter clustering

1. Lipoprotein Lipase S447V polymorphism associates with VLDL, LDL and HDL diameter clustering A.C. Wood a,b, S. Glasserc, E.K. Kabagambea,d, I. E. Boreckie, H. K. Tiwarib, M. Tsai f, P. Hopkins g,J. Ordovash, D. K. Arnett a,da Department of Epidemiology, University of Alabama at Birmingham, School of Public Health, AL. b Section on Statistical Genetics, University of Alabama at Birmingham, School of Public Health, AL. c Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, AL. d Nutrition Obesity Research Center, University of Alabama at Birmingham, School of Public Health, AL. g Division of Statistical Genomics, Department of Genetics, Washington University, School of Medicine, 4444 Forest Park Boulevard – Box 8506, St. Louis, MO,h Department of Laboratory Medicine and Pathology, University of Minnesota, MN i Department of Internal Medicine, University of Utah, Salt Lake City, UT; j JM-USDA-HNRCA, Tufts University, Boston, MA; Introduction Results Hypothesis We aimed to examine whether there were differences in three polymorphisms of the LPL gene between those with small LDL and VLDL (Class 1) and those with small LDL and very large VLDL (Class 2) . Class 2 contained significantly more carriers of the minor allele (25%) of the LPL S447X polymorphism than Class 1 (14%; P=.01; Table 2). There were no differences between the two classes for the LPL M107 or the LPL D9N polymorphisms. Insulin resistance (IR) is cellular resistance to insulin stimulated glucose uptake. To compensate there is increased insulin secretion, known as hyperinsulinema. This leads to a host of metabolic dysfunctions which give rise to 5 features; the presence of 3 of these meets ATP-III criteria for the Metabolic Syndrome (MetS; Table 1). MetS has been shown to predict cardiovascular disease 1,2. The IR, and the individual features of the MetS are associated with smaller LDL and HDL and larger VLDL particles3. Lipoprotein lipase (LPL) is a key enzyme in the VLDL-LDL-IDL cascade. LPL hydrolyzes the TG from VLDL forming LDL and eventually IDL (Figure 1). Identifying genes associated a lipoprotein diameter pattern than marks with the most severe IR features, may help both with prediction and prevention of cardiovascular disease and give insights into the pathways where intervention can be targeted. Figure 1: Partial pathways in lipid metabolism Methods Sample: 251 men and women from the general population Geneticsof Lipid Lowering Drugs and Diet Network (GOLDN) study. Measures: Nuclear Resonance Spectroscopy (NMR) data gave the average diameter for each of three fractions of lipoprotein: VLDL, LDL and HDL in fasting blood. Anthropomorphic data were collected by questionnaire. Genomic DNA was isolated from peripheral blood leukocytes using Puregene DNA reagents following the vendor’s protocol. Three polymorphisms on the LPL gene were typed: M107, D9N and S447X. Methods: Mixed linear models that controlled for age, sex, centre of data collection and family pedigree. Class (1 or 2; table 2) was the outcome variable, and the individual models used LPL polymorphisms as the predictor. Conclusions Previous analysis The LPL S447X polymorphism may be an important variant for understanding the genetic origins of lipoprotein diameter. heterogeneity and its association with the severity of MetS features. Future analysis will take a gene-based approach to get a p-value for the overall gene, not single SNPs. This may contribute to a predictive algorithm to identify those most at risk for incident cardiovascular disease to help reduce the number of cardiovascular events. Previous analysis grouped participants into clusters according to their diameter of fasting VLDL, LDL and HDL particles. Two classes were characterized by similar LDL diameters, but they were distinguished by their VLDL diameters; Table 2). While both classes met the Adult Treatment Panel (ATP) III criteria for MetS, class 2 had features of the MetS associated with more severe insulin resistance (Table 2). Acknowledgements: Thank you to the staff of the GOLDN study for the assistance in data collection and management. This study was funded by NHLBI grant number U01HL072524-04. Dr. A. C. Wood is primarily funded by NIH R01 HL104135-01 (PI: Arnett).  The opinions expressed are those of the authors and do not necessarily represent the views of the NIH or any other organizationReferences 1Arad Y, Newstein D, Cadet F, Roth M, Guerci AD. Association of multiple risk factors and insulin resistance with increased prevalence of asymptomatic coronary artery disease by an electron-beam computed tomographic study. ArteriosclerThrombVascBiol2001;21:2051-58. 2Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW, Collins DC. VA-HIT Study Group. Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care 2003;26:1513-17. 3Garvey WT, Kwon S, Zheng D, Shaughnessy S, Wallace P, Hutto A, Pugh K, Jenkins, AJ, Klein, RL, Liao, Y. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003;52:453-62.